This grant includes several projects whose overall aim is the understanding of the role of hepatitis B virus (HBV) in the pathogenesis of primary hepatocellular carcinoma (PHC). The ultimate objective of this research is the development of primary and secondary prevention measures. We will investigate the application of such methods to Asian immigrants in the Delaware Valley. Another approach is to slow the progress of early asymptomatic PHC so that it is not life shortening. A series of substances extracted from animal blood and plants that react with HBV resurface antigen will be tested for effects on woodchuck hepatitis virus (WHV) infection in woodchucks. To assess the ultimae efficacy of prevention programs, we are establishing a library of worldwide PHC incidence and mortality data. The studies of prior years have substantially supported the hypothesis that persistent infection with HBV is required for development of most cases of PHC. We have described a developmental model of hepatocarcinogenesis that explains the role of HBV. Experiments with WHV in woodchucks based on this concept are proposed. We will also study the replication and production of duck hepatitis B virus (DHBV) in relation to the differentiation and development of the duck embryo. Because of the advantages of animal models of HBV and PHC, we will search for the characterize HBV-like viruses in other animals. We will also investigate the association of HBV or related viruses with diseases of the pancreas in humans. Iron and iron binding proteins affect the response of the host to HBV infection and may also play a role in the development of PHC. We propose several observational and experimental studies to illuminate this relationship. New statistical methods are being developed to analyze these data.